This invention relates to a method for forming particles of a substance. It also relates to a mixing chamber for use in forming particles of a substance.
The use of supercritical fluids in particle forming processes has been described in several documents. A supercritical fluid can be defined as a fluid at or above its critical pressure and critical temperature simultaneously. Such fluids are interesting in particle formation since their solving power of different substances undergoes large changes as a result of changes in the physical characteristics of the surroundings, which characteristics can be relatively easily controlled, such as pressure. This property make supercritical fluid a medium highly appreciated for having a solving power being controllable by pressure and temperature changes, which is particularly useful in extraction and atomization of different substances, such as substances used in pharmacy. Further, supercritical fluids are normally gases under ambient condition, which eliminates the evaporation step needed in conventional liquid extraction.
There are several techniques related to this phenomenon used today, one of which is known as rapid expansion of supercritical solutions (RESS) and another that is known as gas anti-solvent precipitation (GAS). In the GAS technique a substance of interest is dissolved in a conventional solvent, a supercritical fluid such as carbon dioxide is introduced into the solution, leading to a rapid expansion of the volume of the solution. As a result, the solvent power decreases dramatically over a short period of time, triggering the precipitation of particles. Documents referring to this are for example J. W Tom and P. G. Debenedetti in J. Aerosol SCI., 22 (1991), 555-584; P. G. Debenedetti et al in J. Controlled Release, 24(1993), 27-44 and J. W. Tom et al in ACS Symp Ser 514 (1993) 238-257; EP 437 451 and EP 322 687.
A modification of the GAS system has recently been developed, which is called the SEDS (solution enhanced dispersion by supercritical fluid) process, which utilises supercritical fluid technologies for particle formation.
This technique is described in WO95/01221, which reveals a method for the formation of a particulate product, which comprises the co-introduction of a supercritical fluid and a vehicle system comprising at least one substance in solution or suspension into a particle formation vessel. The temperature and pressure inside the particle formation vessel are controlled, such that dispersion and extraction of the vehicle occur substantially simultaneously by the action of the supercritical fluid.
The method described in the aforementioned document is particularly developed for use in Gas Anti Solvent (GAS) techniques. These techniques are useful in situations where the solid of interest does not dissolve in, or has very low solubility in a supercritical fluid. The solute is therefore in a first step dissolved in a conventional solvent. The solution of the solvent and the substance is commonly known under the term xe2x80x9cvehicle systemxe2x80x9d. The term xe2x80x9cvehiclexe2x80x9d is herein a fluid, which dissolves a solid or solids to form a solution, or which forms a suspension of a solid or solids, which do not dissolve or have a low solubility in the fluid. The vehicle can be composed of one or more fluids.
In a second step of the procedure, the vehicle is extracted by the supercritical fluid, which has a sufficient solubility for the vehicle in concern when held in a supercritical condition. As a result, extraction and droplet formation of the vehicle occurs substantially simultaneously by the action of the supercritical fluid. The particles thus formed by the substance previously carried in the vehicle system are collected in a particle vessel and the remaining supercritical fluid and vehicle products can optionally be brought through a cleaning system for possible reuse. The term xe2x80x9cparticlexe2x80x9d as used herein can include products in a single-component or multi-component, as mixtures of one component in a matrix of another form.
In the description of the method described above, the importance of maintaining control over the working conditions, especially the pressure is set out. It is thus necessary to eliminate any uncontrolled pressure fluctuation across the particle formation vessel and ensure a uniform dispersion of the vehicle. Through a high degree of control of parameters such as temperature, pressure and flow rate of both vehicle system and supercritical fluid and the simultaneous co-introduction of the vehicle system and the supercritical fluid into the particle formation vessel, droplet formation occurs when the fluids come into contact with one another.
In the document WO95/01221 is further an apparatus for performing the method described. The apparatus is provided with means for co-introduction of the vehicle system and the supercritical fluid into the particle formation vessel. This means consists of a nozzle, having coaxial passages serving to carry the flow of the vehicle system and of the supercritical flow, respectively. The outlet end of the particle formation chamber is conical, with an angle of taper typically in the range of 10 to 50 degrees. The document teaches further that an increase in the angle may be used for increasing the velocity of the super-critical fluid introduced to the nozzle and hence the amount of physical contact between the supercritical fluid and the vehicle system. It is further imposed that control of parameters such as size and shape in the resulting particulate product will be dependent upon variables including the flow rates of the supercritical fluid and/or the vehicle system comprising the substance, the concentration of the substance in the vehicle system, and the temperature and pressure inside the particle formation vessel.
In another patent document, WO96/00610, the method is improved by introducing a second vehicle, which is both substantially miscible with the first vehicle and substantially soluble in the supercritical fluid. The corresponding apparatus is consequently provided with at least three coaxial passages. These passages terminate adjacent or substantially adjacent to one another at the outlet end of the nozzle, which end is communicating with a particle formation vessel. In one embodiment of the nozzle the outlet of at least one of the inner nozzle passages is located a small distance upstream (in use) of the outlet of one of its surrounding passages. This allows a degree of mixing to occur within the nozzle between the solution or suspension, that is the first vehicle system, and the second vehicle. This pre-mixing of the solution and the second vehicle does not involve the supercritical fluid. It is in fact believed that the high velocity supercritical fluid emerging from the outer passage of the nozzle causes the fluids from the inner passages to be broken up into fluid elements. From these fluid elements the vehicles are extracted by the supercritical fluid, which results in the formation of particles of the solid previously solved in the first vehicle. The useful maximal taper of the conical end is in this document also augmented up to 60 degrees.
Another technique for particle precipitation using near-critical and supercritical antisolvents has later been described in WO97/31691. This document mentions the use of specialized nozzles for creating extremely fine droplet sprays of the fluid dispersions. The method involves passing the fluid dispersion through a first passageway and a first passageway outlet into a precipitation zone, which contains an antisolvent in a near- or supercritical condition. Simultaneously an energizing gas stream is passed along and through a second passageway outlet proximal to the first fluid dispersion outlet. The passage of the energizing gas stream generates high frequency waves of the energizing gas adjacent to the first passageway outlet in order to break up the fluid dispersion into small droplets.
The disclosed prior art of producing small particles by use of supercritical fluid as an antisolvent to release a desired substance from a solution or suspension, do all try to achieve control over parameters such as pressure and temperature, in order to control the morphology, size and size distribution of the particles formed of the substance concerned.
The requests from for example the pharmaceutical industry for production of small particles with a narrow size distribution and a specialized morphology do however invoke the need for even better particle formation techniques than those mentioned in the disclosed prior art. New substances with new behavior in particle formation do also require new and improved methods for controlling and industrially accomplishing the particularization needed. The aim of this invention is to provide a method and a mixing chamber for production of small particles with a narrow size-distribution and uniform morphology.
The present invention relates to a method for forming particles of a substance, comprising the step of introducing into a mixing chamber, in which the temperature and pressure are controlled, a fluid gas and at least one vehicle system comprising at least one substance in solution or suspension such that droplet formation and extraction of the vehicle occur substantially simultaneously by the action of the fluid gas; wherein turbulence is induced in at least one of said fluid gas and said vehicle system so as to create a controlled disorder in the flow of the at least one of the fluid gas or the vehicle system in order to control the particle formation in said mixing chamber, said controlled disorder being created by at least one flow perturbation means.
Herein, the definition to a xe2x80x9cfluid gasxe2x80x9d includes material in its supercritical and near-supercritical state as well as compressed gases. The fluid gas can be, but is not limited to, carbon dioxide, nitrous oxide, sulphur hexafluoride, xenon, ethane, ethylene, propane, chlorotrifluoromethane, and trifluoromethane. For example, the lower temperature limit for a near super-critical state is for carbon dioxide 0.65xc3x97Tc and for propane 0.30xc3x97Tc, where Tc is the critical temperature for the specific substance.
When deliberately creating turbulence or a disorder in the flow of fluid gas or vehicle system one differs remarkably from prior art of the area. Turbulence is known to be an extremely sensitive condition, in which the local pressures are difficult to describe in detail even in the case of ideal, incompressible gases. Using turbulence in combination with fluid gas, whose properties are known to alter dramatically with changing conditions such as pressure, one could expect a chaotic state lacking the control needed for creating small and homogeneous particles. However, it has now been shown that creation of turbulence in the fluid gas or the vehicle system before introduction into the particle formation chamber has a remarkable and stable effect on particle size and distribution.
Preferably, the turbulence is controlled so as to form the desired particles of the at least one, specific substance. The turbulence does probably need to be adjusted to different substances and vehicles so as to create particles with the properties wanted.
The controlled disorder can advantageously be created by the interaction of at least one of said fluids with the interior of the mixing chamber. The design of the mixing chamber should then be adapted to create a controlled disorder in at least one of the fluids, when said fluid encounters the interior of the mixing chamber.
Preferably, turbulence in at least one of said fluid gas and said vehicle system is occurring in a region near or adjacent to an outlet orifice of said mixing chamber, where nucleation is believed to occur. The effect on the created particles seems to be related to the altered crystallization environment that is established when at least one of the fluid flows is somewhat disturbed. It might also increase intermixing of the different fluids and hence the overall surfaces available for reaction between fluids.
The invention also relates to a particle formation chamber or mixing chamber according to the preamble and wherein at least one flow perturbation means is disposed for interacting with at least one of the fluid gas or vehicle system supplied by the at least one supply member so as to induce turbulence in the at least one of the fluid gas or vehicle system for creating a controlled disorder in the flow of the at least one of the fluid gas or the vehicle system in order to control the particle formation in said mixing chamber. The flow perturbation device is meant to constitute an obstacle for the flow in the passage of either of the fluids, and thus create the turbulence required, which in turn will affect the physical properties of the particles formed in the particle formation chamber.
Advantageously, said flow perturbation means is designed so as to induce a turbulence that is controlled so as to form the desired particles of the at least one, specific substance. Different substances with varying properties appear to need different kinds and amounts of turbulence in order to optimize the particle formation.
The flow perturbation means can be formed in the interior of the mixing chamber. The fluids entering the mixing chamber will thus encounter the perturbation means inside of the mixing chamber.
Preferably, the flow perturbation means are disposed so as to create turbulence in at least one of said supercritical fluid and said vehicle system, in a region near or adjacent to said outlet part of said mixing chamber, where nucleation is believed to occur.
Preferably, the flow perturbation means consists of a projecting member in the interior of the chamber. Such a member will constitute an effective obstacle for the flow, and thus create turbulence.
Advantageously, said flow perturbation means are constituted by at least one shelf in the wall of the mixing chamber, said shelf opposing the direction of said flow, when in use. Such a shelf will efficiently return the kinetic energy of the flow in a back-flow direction thus creating turbulence in the area around said shelf.
Preferably, the flow perturbation means is constituted by at least two separate members. Such members can be two shelves in the wall of the mixing chamber or one shelf and at least one baffle extending from said mixing chamber wall. The choice of flow perturbation means is preferably adapted to the substance of which particles are to be formed.
Preferably, the mixing chamber can comprise first and second body parts, which are detachably coupled to each other.
Manufacturing the mixing chamber in two separate parts provides the advantage of easy cleaning of the mixing chamber. In prior art, there is often a problem with particles clogging in the mixing chamber, and shutting the outlet orifice of the mixing chamber. When a two-piece mixing chamber is used, such particles can be easily removed by simply opening and cleaning the mixing chamber.